Cannabidiol and Prolonged Exposure

Prolonged exposure therapy (PE) is among the most efficacious treatments for PTSD and is
designated as a VA/DoD frontline treatment. However, PE does not always lead to clinically
meaningful symptom reductions in Veterans with PTSD. Successful PE treatment relies on
extinction learning, which is often impaired in patients with PTSD. Cannabidiol (CBD) is a
non-intoxicating phytocannabinoid. Administration of specific phytocannabinoids, like CBD,
increase extinction learning in patients with PTSD, and could increase the speed and
effectiveness of PE therapy. CBD also modulates 5-HT1A, which may directly improve
hyperarousal/insomnia symptoms, and improve engagement and retention in treatment. Given
these findings, adjunctive administration of CBD+PE could improve response rates to PE and
reduce the number of sessions of PE needed to reach clinically meaningful change. The
proposed study is designed to test the efficacy of using CBD in conjunction with PE for the
treatment of PTSD in US Military Veterans. A randomized, controlled, double-blind study will
compare Veterans who receive PE+CBD to PE+placebo. Participants will include 136 male and
female Veterans from all service eras with PTSD. The primary hypothesis is that PE+CBD will
reduce PTSD symptoms to a greater degree than PE+placebo.

Inclusion Criteria:

- Over the age of 18 at the time of screening.

- Judged by the study physician to be in generally good health.

- Meet clinical criteria for Posttraumatic Stress Disorder (PTSD) on the
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).

- Body mass index between 18-35 kg/m2.

- Negative urine pregnancy test.

Exclusion Criteria:

- History of significant allergic condition, significant drug-related hypersensitivity,
or allergic reaction to cannabinoids.

- Used cannabis, synthetic cannabinoid, cannabinoid analogue, or any CBD or
THC-containing product within 30 days of eligibility screening.

- Patient has had a change in psychopharmacotherapy regimen in the last 4 weeks, or has
any plans to change regimen over the course of the study.

- Patient is engaged in trauma-related psychotherapy for PTSD.

- Current or past DSM-5 diagnosis of dissociative identity disorder, eating disorder
with active purging, personality disorders, primary psychotic disorder, or bipolar
affective disorder type 1.

- Patient is currently prescribed medications with possible CBD-drug interactions.

- History of actual suicide attempt in the last 5 years.

- Obstructive sleep apnea.

- Positive drug screen for THC, barbiturates, amphetamines, benzodiazepines, and/or
opiates.

- History of treatment for, or evidence of, alcohol or drug abuse within the past year
or regular alcohol consumption exceeding recommended limits.

- Lifetime history of Cannabis Use Disorder.

- Pregnant or breastfeeding.